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'New diabetes pill' still years away

“A daily pill that could treat or even cure diabetes is a step closer after scientists discovered how to reverse the condition,” reported the Daily Express.

It went on to say that this “groundbreaking finding” has “huge implications for the health of the nation”.

This study found that injecting a naturally occurring chemical called NMN (nicotinamide mononucleotide) into mice with type 2 diabetes improved their disease. In female mice fed a high-fat diet, NMN restored the mice’s glucose tolerance to normal. The effects in male mice fed a high-fat diet were not as great. NMN also improved glucose tolerance on male mice with age-related diabetes.

As the researchers acknowledge, further research is required to check whether the biological process behind this research also occurs in humans, and that administering this chemical will be safe and have a similar beneficial effect. If this research is successful, it is still likely to take many years to develop from this initial research in animals to a pill for type 2 diabetes in humans.

Where did the story come from?

The study was carried out by researchers from Washington University School of Medicine and was funded by a number of health institutes, including the National Institute on Aging.

The research was published in the peer-reviewed journal Cell.

The news coverage by the Daily Express was quite sensationalist and may have overemphasised the significance of these findings for humans. For instance, the report says that “the groundbreaking finding effectively means that the obese and those at risk of getting type 2 diabetes could one day take a tablet to stop the condition developing”. This and other statements may give the impression that a diabetes pill is just around the corner, which is not the case. This research was in mice and did not test the effect of a pill on humans. It merely represents the very first stage of a long process.

What kind of research was this?

This research was an animal study using mice conditioned to have type 2 diabetes through a high-fat diet. It aimed to investigate the effect of a specific chemical, nicotinamide mononucleotide or NMN, on diabetes.

Diabetes develops when the body cannot regulate glucose levels in the blood. Glucose is used by cells for energy and is controlled by the hormone insulin. Type 2 diabetes usually affects people over 40 years old and develops when the body either doesn’t make enough insulin to control glucose levels, or when the insulin does not work properly. The disease is typically associated with obesity and with a diet high in calories and fat, but can also develop due to the natural ageing process.

The research focused on one particular biological pathway involved in the metabolism of glucose, revolving around a chemical called nicotinamide adenine dinucleotide (NAD+). This chemical is produced in the body from other chemicals, one of which is NMN, the chemical tested in this study. Previous research indicates that this pathway is affected by changes in energy intake, for example by fasting and diet restriction.

Small animal studies are a useful first step to investigate disease processes that also occur in humans as many of the biological processes of mice and men are similar. However, there are still important differences between the species and so findings demonstrated in mice may not be entirely representative of what would happen in humans. To translate findings from mice to humans, properly controlled human research trials are typically carried out, and only after any major safety concerns are ruled out in animals.

What did the research involve?

In this study, mice were fed high-fat diets until they developed type 2 diabetes to mimic the human disease. The researchers then examined whether this diabetes could be reversed by giving the mice NMN, a key compound in the biological pathway under investigation.

NMN was given by injection at a dose of 500mg/kg bodyweight to the mice for 7-10 consecutive days.

The researchers went on to investigate how NMN might influence insulin sensitivity in the liver, specifically in female mice, and what enzymes and genes might be important in this process.

They also investigated what the effect of NMN would be in mice that developed diabetes naturally in old age.

What were the basic results?

The high-fat diet successfully induced diabetes in the mice, with the female mice developing diabetes before the male mice. The high-fat diet also significantly reduced the production of NAD+ in the mice’s liver and fat tissue.

In female mice, the researchers found that administering NMN restored NAD+ levels to normal and also completely restored their glucose tolerance to normal levels (glucose intolerance is the main characteristic of diabetes). They found the female mice were also more sensitive to insulin (one of the main hormones responsible for regulating glucose levels in the body) after receiving NMN.

In diabetic male mice NMN also restored NAD+ levels and improved glucose tolerance, but the effects were not as great. In a further gender difference, insulin tolerance remained unchanged in males after NMN treatment.

The effects of NMN were seen for both young and old mice and did not adversely affect non-diabetic mice. This and other findings led the researchers to suggest that NMN might also be effective in age-induced diabetes (diabetes that develops due to old age rather than a high-calorie diet). They carried out similar experiments in male mice with age-related diabetes and found that one dose of NMN restored glucose tolerance in these mice.

The researchers went on to investigate how NMN increases insulin sensitivity in the liver, specifically in female mice. Insulin normally prompts the liver to take up glucose and store it in a form called glycogen. They found that many biological processes and changes in the activity of genes that were affected by the high-fat diet were reversed by giving NMN, including those directly involved in processing fats. They suggest that a key enzyme, SIRT1, was important in how NMN acted to increase insulin sensitivity in the liver.

How did the researchers interpret the results?

The researchers concluded that production of NAD+ is reduced in mice fed a high-fat diet and that this contributes to the development of type 2 diabetes. They report that they show “proof of the concept” that giving NMN can restore NAD+ levels and that this could be an effective intervention to treat diet and age-induced type 2 diabetes.

They suggest that the differences observed between males and females might be due to differences in sex-specific hormones, which are known to influence insulin sensitivity and glucose regulation.

Conclusion

This early stage animal research demonstrated a positive effect of administering NMN to mice with type 2 diabetes caused by a high-fat diet or ageing. The effects were more beneficial in female mice fed a high-fat diet. This research highlights the importance of NMN in this specific process and proposes a partial biological explanation for how it works. This will help guide future research to fully explore the processes involved.

The following points are worth considering when interpreting the findings of this research:

Small animal studies are a useful first step to investigate disease processes, but findings demonstrated in mice are not always representative of what would happen in humans. To translate findings from mice to men, properly controlled human research trials are needed and only after any potential safety concerns are addressed.

It is not clear whether the biological pathway investigated in this study of mice behaves in a similar way in humans, or whether the beneficial effect of NMN would be replicated in humans. Research on humans is needed to demonstrate this.

NMN was more effective in female mice with diet-induced diabetes; more modest benefits were seen in males. This highlights that more research is needed to understand fully the biological mechanisms behind the effect of NMN and the difference observed between males and females.

It is not clear from this research how long the effect of the NMN injections would last in mice, particularly if the mice continued to have a high-fat diet.

This very early stage research provides new understanding and focus for future research on the biological processes of type 2 diabetes and the potential role of NMN in treating this. However, the effect of NMN has not yet been demonstrated in humans and so the development of a potential pill is likely to be a long way off and dependent on first demonstrating safety and sufficient efficacy in animals.